Stable fixed dose pharmaceutical composition comprising mometasone and olopatadine

ABSTRACT

The present invention relates to a stable fixed dose aqueous pharmaceutical composition (e.g., contained in a container) for nasal administration to a human, comprising mometasone or its salt, olopatadine or its salt. The composition may further include a hydrocolloid. The invention also relates to a process for preparing the pharmaceutical composition, and the use of the pharmaceutical composition in the treatment of rhinitis in a subject.

CROSS-REFERENCE TO RELATED APPLICATIONS

This patent application claims priority to (1) Indian Provisional PatentApplication number 2975/MUM/2013 (filed on Sep. 13, 2013), and (2)International Patent Application No. PCT/IB2014/064251 (filed on Sep. 4,2014), each of which is hereby incorporated by reference.

FIELD OF THE INVENTION

The present patent application relates to a stable fixed dose, aqueouspharmaceutical composition for nasal administration to a humancomprising mometasone or its salt and olopatadine or its salt. Theapplication also relates to a process for preparing the pharmaceuticalcomposition and its use in the treatment of rhinitis in a subject.

BACKGROUND OF THE INVENTION

Rhinitis is a medical term for irritation and inflammation of the mucousmembrane inside the nose Rhinitis may cause additional symptoms, such assneezing, nasal itching, coughing, headache, fatigue, malaise, andcognitive impairment.

Olopatadine hydrochloride is chemically described as(Z)-11-[3-(dimethylamino)propylidene]-6,11-dihydrodibenz[b,e]oxepin-2-aceticacid hydrochloride, as disclosed in U.S. Pat. Nos. 4,871,865 and4,923,892. It is commercially available in the U.S as PATANASE® NasalSpray, which contains 0.6% w/v olopatadine in a non-sterile aqueoussolution. It is indicated for the relief of the symptoms of seasonalallergic rhinitis in adults and children 6 years of age and older.

Mometasone furoate is a glucocorticosteroid used topically to reduceinflammation of the skin or in the airways. Mometasone furoate iscommercially available as NASONEX® in the U.S. as a nasal sprayindicated for upper respiratory conditions such as nasal sinusinflammation. It is available as 50 mcg in a metered-dose, manual pumpspray unit containing an aqueous suspension of mometasone furoatemonohydrate equivalent to 0.05% w/w mometasone furoate.

WO 2011/141929 discloses an aqueous nasal spray solution comprisingfluticasone and olopatadine.

U.S. Pat. No. 6,127,353 discloses a pharmaceutical composition ofmometasone furoate monohydrate.

U.S. Pat. Nos. 7,977,376 and 8,399,508 disclose a topical formulation ofolopatadine.

WO 2014/092346 discloses a bitter taste masked pharmaceuticalcomposition comprising a corticosteroid, an antihistamine and stevia.

WO 2006/057769 discloses a method of delivering a nasal spray containingolopatadine.

WO 2010/025236 discloses a combination of a nasal steroid and a nasalantihistamine for the treatment of viral upper respiratory tractinfections, upper respiratory infections, and common colds.

There still exists a need for easy to use and effective treatments ofrhinitis.

SUMMARY OF THE INVENTION

The present invention relates to a stable fixed dose, aqueouspharmaceutical composition for nasal administration to a human. Thecomposition comprises mometasone or its salt and olopatadine or itssalt. The pharmaceutical composition may be contained within a containersuitable for nasal administration.

One embodiment is a stable fixed dose, aqueous pharmaceuticalcomposition (e.g., contained in a container) for nasal administration toa human, where the composition comprises about 0.001% w/w to about 0.075w/w mometasone or its salt and about 0.5 w/w to about 0.8% w/wolopatadine or its salt. The pharmaceutical composition may be in theform of a solution or a suspension, but preferably the composition is inthe form of a suspension (more preferably, a single phase suspension),wherein mometasone or its salt is present in particle form andolopatadine or its salt is present in dissolved form. In one aspect, themometasone or its salt and olopatadine or its salt are present in aweight ratio of about 1:3 to about 1:106, or from about 1:5 to about1:53, or preferably from about 1:5 to about 1:36.

The composition preferably also includes a hydrocolloid. In oneembodiment, the composition is a suspension and includes a hydrocolloidin a sufficient amount to prevent phase separation (i.e., separation ofthe particles and solution) after 3 or 6 months of storage at 25±2° C.and 60%±5% relative humidity (RH) or at 40±2° C. and 75%±5% RH. In oneembodiment, the aqueous pharmaceutical composition is a single phasesuspension which remains a single phase suspension even after 3 or 6months of storage at 25±2° C. and 60%±5% RH or at 40±2° C. and 75%±5%RH.

Another embodiment is a stable fixed dose, aqueous pharmaceuticalcomposition (e.g., contained in a container) for nasal administration toa human, where the composition comprises about 0.001% w/w to about0.075% w/w mometasone furoate monohydrate and about 0.5 w/w to about0.8% w/w olopatadine hydrochloride.

Yet another embodiment is a stable fixed dose, aqueous pharmaceuticalsuspension composition (e.g., contained in a container) for nasaladministration to a human, where the composition comprises about 0.025%w/w to about 0.05% w/w mometasone or its salt, about 0.6% w/w to about0.7% w/w olopatadine or its salt and a hydrocolloid.

Yet another embodiment is a stable fixed dose, aqueous pharmaceuticalsuspension composition (e.g., contained in a container) for nasaladministration to a human, where the composition comprises about 0.025%w/w to about 0.05% w/w mometasone or its salt, about 0.6% w/w to about0.7% w/w olopatadine or its salt and a hydrocolloid which includescarboxymethylcellulose sodium and xanthan gum. The hydrocolloid may bepresent at a concentration of at least about 0.1% w/w of thecomposition.

One embodiment is a stable fixed dose, aqueous pharmaceutical suspensioncomposition (e.g., contained in a container) for nasal administration toa human, comprising about 0.025 w/w to about 0.05 w/w mometasonefuroate, about 0.6% w/w to about 0.7% w/w olopatadine hydrochloride anda hydrocolloid, where the hydrocolloid is xanthan gum. The xanthan gummay be present at a concentration of at least about 0.1% w/w, orpreferably between about 0.1% w/w to about 3% w/w of the composition.

Another embodiment is a stable fixed dose, aqueous pharmaceuticalsuspension composition (e.g., contained in a container) for nasaladministration to a human, comprising about 0.025% w/w to about 0.05%w/w mometasone furoate, about 0.6% w/w to about 0.7% w/w olopatadinehydrochloride and a hydrocolloid, where the hydrocolloid comprisessodium carboxymethyl cellulose. The sodium carboxymethyl cellulose maybe present at a concentration of at least about 0.1% w/w, or preferablybetween about 0.1% w/w to about 3% w/w of the composition.

Yet another embodiment is a stable fixed dose aqueous pharmaceuticalcomposition in the form of suspension (e.g., contained in a container)for nasal administration to a human, comprising mometasone or itspharmaceutically acceptable salt, olopatadine or its pharmaceuticallyacceptable salt, a hydrocolloid at a concentration of at least about0.1% w/w of the composition and a pharmaceutical acceptable excipient.

Suitable pharmaceutical acceptable excipients include, but are notlimited to, chelating agents, preservatives, buffers, surfactants,isotonicity agents, taste masking agents, antioxidants, humectants, pHadjusting agents, and mixtures thereof.

In one embodiment, the pharmaceutical composition has a pH between about3.3 and about 4.1, or between about 3.5 and about 3.9. The inventorsdiscovered that the olopatadine hydrochloride crystallizes out of thefixed dose combination aqueous suspension at a pH of 5 to 5.5. Theolopatadine hydrochloride, however, remains dissolved in the aqueoussuspension at a pH of about 3.3 to about 4.1.

The aqueous pharmaceutical composition preferably is substantially freeof crystals of olopatadine hydrochloride. In one embodiment, the aqueouspharmaceutical composition contains less than 2%, less than 1%, lessthan 0.5%, less than 0.2%, or less than 0.1% of crystalline olopatadinehydrochloride, based on the 100% total weight of olopatadinehydrochloride in the composition. In another embodiment, the aqueouspharmaceutical composition is substantially free of crystals ofolopatadine hydrochloride after 3 or 6 months of storage at 25±2° C. and60%±5% RH or at 40±2° C. and 75%±5% RH. In yet another embodiment, theaqueous pharmaceutical composition contains less than 2%, less than 1%,less than 0.5%, less than 0.2%, or less than 0.1% of crystallineolopatadine hydrochloride, based on the 100% total weight of olopatadinehydrochloride in the composition, after 3 or 6 months of storage at25±2° C. and 60%±5% RH or at 40±2° C. and 75%±5% RH.

The osmolality of the pharmaceutical composition may range between about200 mOsm/kg to about 400 mOsm/kg, or about 250 mOsm/kg to about 350mOsm/kg.

The viscosity of the pharmaceutical composition may range from about 10cps to about 200 cps or preferably from about 20 cps to about 150 cps.

In yet another aspect, the pharmaceutical composition is in the form ofsuspension and contains mometasone furoate in particles having a meanparticle size in the range of from about 1 μm to about 20 μm, orpreferably from about 1 μm to about 15 μm. In an aspect, the suspensionpharmaceutical composition of the present invention has mean particlesize of less than 15 μm when determined by microscopy technique.

In yet another aspect, the pharmaceutical composition, when delivered asa nasal spray has spray characteristics comprising a spray patternhaving a longest axis of about 15-75 mm, a shortest axis of about 10-65mm, and an ellipticity of about 1-2.

Another embodiment is a stable fixed dose pharmaceutical composition inthe form of a suspension (e.g., contained in a container) for nasaladministration to a human, comprising mometasone furoate monohydrate,olopatadine hydrochloride and a hydrocolloid which comprises xanthan gumat a concentration of about 0.3% w/w of the composition, wherein thecomposition has a pH between about 3.5 to about 3.9.

Yet another embodiment is a stable fixed dose pharmaceutical compositionin the form of suspension (e.g., contained in a container) for nasaladministration to a human, comprising mometasone furoate monohydrate,olopatadine hydrochloride and a hydrocolloid which comprises sodiumcarboxymethyl cellulose at a concentration of about 0.5% w/w of thecomposition, wherein the composition has a pH between about 3.5 to about3.9.

In a further embodiment, the stable fixed dose, aqueous pharmaceuticalcomposition is contained in a sprayer, and on delivering a spray of thecomposition to a human nose results in a spray pattern having a longestaxis of 15-75 mm, a shortest axis of 10-65 mm, and an ellipticity of1-2.

One embodiment is a stable fixed dose, aqueous pharmaceuticalcomposition comprising mometasone furoate monohydrate, olopatadinehydrochloride and optionally a hydrocolloid contained in a sprayer,wherein each spray of the aqueous pharmaceutical composition provides(i) mometasone furoate monohydrate equivalent to about 50 mcg ofmometasone furoate and (ii) olopatadine hydrochloride equivalent toabout 600 mcg olopatadine.

Another embodiment is a method for treating rhinitis, or foradministering mometasone and olopatadine. The method includes spraying astable fixed dose, aqueous pharmaceutical composition comprisingmometasone furoate monohydrate, olopatadine hydrochloride and optionallya hydrocolloid such that each spray of the aqueous pharmaceuticalcomposition provides (i) mometasone furoate monohydrate equivalent toabout 50 mcg of mometasone furoate and (ii) olopatadine hydrochlorideequivalent to about 600 mcg olopatadine.

Yet another embodiment is a stable fixed dose, aqueous pharmaceuticalcomposition comprising mometasone furoate monohydrate, olopatadinehydrochloride and optionally a hydrocolloid contained in a sprayer,wherein each spray of the aqueous pharmaceutical composition provides(i) mometasone furoate monohydrate equivalent to about 25 mcg ofmometasone furoate and (ii) olopatadine hydrochloride equivalent toabout 600 mcg olopatadine.

Yet another embodiment is a method for treating rhinitis, or foradministering mometasone and olopatadine. The method includes spraying astable fixed dose, aqueous pharmaceutical composition comprisingmometasone furoate monohydrate, olopatadine hydrochloride and optionallya hydrocolloid such that each spray of the aqueous pharmaceuticalcomposition provides (i) mometasone furoate monohydrate equivalent toabout 25 mcg of mometasone furoate and (ii) olopatadine hydrochlorideequivalent to about 600 mcg olopatadine.

In an embodiment, the present invention relates to a stable fixed dosepharmaceutical aqueous suspension composition (e.g., contained in acontainer) for nasal administration to a human, where the compositioncomprises (1) about 0.025% w/w mometasone furoate monohydrate, (2) about0.665% w/w olopatadine hydrochloride, (3) a hydrocolloid selected fromabout 0.3% w/w of xanthan gum and about 0.5% w/w carboxymethyl cellulosesodium (4) about 0.02% w/w benzalkonium chloride, (5) about 0.4% w/wsodium chloride, (6) about 0.01% w/w di-sodium edetate, (7) about 0.94%w/w sodium phosphate heptahydrate, and (8) about 0.01% w/w polysorbate80.

Another embodiment is a stable fixed dose pharmaceutical aqueoussuspension composition (e.g., contained in a container) for nasaladministration to a human, where the composition comprises (1) about0.050% w/w mometasone furoate monohydrate, (2) about 0.665% w/wolopatadine hydrochloride, (3) a hydrocolloid selected from about 0.3%w/w of xanthan gum and about 0.5 w/w carboxymethyl cellulose sodium, (4)about 0.02% w/w benzalkonium chloride, (5) about 0.4% w/w sodiumchloride, (6) about 0.01% w/w di-sodium edetate, (7) about 0.94% w/wsodium phosphate heptahydrate, and (8) about 0.01% w/w polysorbate 80.

Yet another embodiment is a stable fixed dose pharmaceutical aqueoussuspension composition (e.g., contained in a container) for nasaladministration to a human, where the composition comprises (1) about0.025% w/w mometasone furoate monohydrate, (2) about 0.665% w/wolopatadine hydrochloride, (3) a hydrocolloid selected from about 0.3%w/w of xanthan gum and about 0.5 w/w carboxymethyl cellulose sodium, (4)about 1% w/w to about 1.2% w/w mixture of microcrystalline cellulose andcarboxymethyl cellulose sodium, (5) about 0.02% w/w benzalkoniumchloride, (6) about 0.4% w/w sodium chloride, (7) about 0.01% w/wdi-sodium edetate, (8) about 0.94% w/w sodium phosphate heptahydrate,and (9) about 0.01% w/w polysorbate 80.

Yet another embodiment is a stable fixed dose pharmaceutical aqueoussuspension composition (e.g., contained in a container) for nasaladministration to a human, where the composition comprises (1) about0.050% w/w mometasone furoate monohydrate, (2) about 0.665% w/wolopatadine hydrochloride, (3) a hydrocolloid selected from about 0.3%w/w of xanthan gum and about 0.5 w/w carboxymethyl cellulose sodium, (4)about 1% w/w to about 1.2% w/w mixture of microcrystalline cellulose andcarboxymethyl cellulose sodium, (5) about 0.02% w/w benzalkoniumchloride, (6) about 0.4% w/w sodium chloride, (7) about 0.01% w/wdi-sodium edetate, (8) about 0.94% w/w sodium phosphate heptahydrate,and (9) about 0.01% w/w polysorbate 80.

Yet another embodiment is a stable suspension suitable for nasaladministration to a human, comprising (a) an aqueous solvent, (b)particles of mometasone furoate suspended in the solvent, the particleshaving a mean particle size of from about 1 to about 20 μm, (c)olopatadine hydrochloride dissolved in the solvent, and (d) ahydrocolloid, the suspension having a viscosity in the range of about 20cps to about 150 cps. In one preferred embodiment, the suspension has apH of about 3.5-3.9, and osmolality in the range of about 250 mOsm/kg toabout 350 mOsm/kg. In one embodiment, the suspension further comprises achelating agent, a preservative, a buffer, a surfactant, an isotonicityagent, and optionally a pH adjusting agent.

Preferably, the suspensions of the present invention have only one phase(i.e., they are preferably a single phase suspension).

In another embodiment, the present invention relates to a method oftreating rhinitis in a human in need thereof comprising administering bythe nasal route a stable fixed dose, aqueous pharmaceutical compositionof the present invention. In one embodiment, the pharmaceuticalcomposition comprises about 0.025% w/w to about 0.05 w/w mometasone orits salt and about 0.5% w/w to about 0.8% w/w olopatadine or its salt,as disclosed herein.

In a further embodiment, the present invention relates to use of apharmaceutical composition of the present invention for the treatment ofrhinitis in a human in need thereof. For example, one embodiment is theuse of about 0.025% w/w to about 0.05 w/w mometasone or its salt andabout 0.5 w/w to about 0.8% w/w olopatadine or its salt in thepreparation of a stable fixed dose, aqueous pharmaceutical composition(e.g., contained in a container) for the treatment of rhinitis in ahuman in need thereof.

In a further embodiment, the present invention relates to a stable fixeddose, aqueous pharmaceutical composition (e.g., contained in acontainer) for nasal administration comprising about 0.025 w/w to about0.05 w/w mometasone or its salt and about 0.5 w/w to about 0.8% w/wolopatadine or its salt for the treatment of rhinitis in a human in needthereof.

In a further embodiment, the present invention relates to a kitcomprising a stable fixed dose, aqueous pharmaceutical compositioncontained in a container, for nasal administration and a package insertcontaining instructions about the use of the pharmaceutical composition.

DETAILED DESCRIPTION OF THE INVENTION Definitions

The terms used herein are defined as follows. If a definition set forthin the present application and a definition set forth in a provisionalapplication from which priority is claimed are in conflict, thedefinition in the present application shall control the meaning of theterms.

The term “effective amount” when used in connection with an activeingredient denotes an amount of the active ingredient that, whenadministered to a subject for treating rhinitis, produces an intendedtherapeutic benefit in a subject. The term “active ingredient” (usedinterchangeably with “active” or “active substance” or “drug”) as usedherein includes mometasone or its salt and olopatadine or its salt.

In the context of present invention, the effective amount of mometasoneor its salt can range from about 0.01 mg to about 10 mg or preferablyfrom about 0.02 mg to about 5 mg. The effective amount of olopatadine orits salt can range from about 0.05 mg to about 20 mg, or preferably fromabout 0.1 mg to about 15 mg.

In an aspect of this invention, for daily administration by the nasalroute, the effective amount of mometasone or its salt can range fromabout 10 mcg to about 500 mcg, or preferably from about 20 mcg to about400 mcg, and that for olopatadine or its salt can ranges from about 50mcg to about 7000 mcg, or preferably from about 100 mcg to about 5400mcg.

By “salt” or “pharmaceutically acceptable salt”, it is meant those saltsand esters which are, within the scope of sound medical judgment,suitable for use in contact with the tissues of humans and lower animalswithout undue toxicity, irritation, and allergic response, commensuratewith a reasonable benefit to risk ratio, and effective for theirintended use. Representative acid additions salts include hydrochloride,furoate, hydrobromide, sulphate, bisulphate, acetate, oxalate, valerate,oleate, palmitate, stearate, laurate, borate, benzoate, lactate,phosphate, tosylate, mesylate, citrate, maleate, fumarate, succinate,tartrate, ascorbate, glucoheptonate, lactobionate, and lauryl sulphatesalts. Representative alkali or alkaline earth metal salts includesodium, calcium, potassium and magnesium salts.

The term “treating” or “treatment” as used herein includes theprophylaxis, mitigation, prevention, amelioration, or suppression of adisorder modulated by mometasone or its salt or olopatadine or its salt,or by a combination of the two in a mammal.

By “pharmaceutically acceptable excipients”, it is meant any of thecomponents of a pharmaceutical composition other than the activeingredients and which are approved by regulatory authorities or aregenerally regarded as safe for human or animal use.

As used herein, the term “average particle size” (or synonymously, “meanparticle size”) refers to the distribution of particles, wherein about50 volume percent of all the particles measured have a size less thanthe defined average particle size value and about 50 volume percent ofall particles measured have a particle size greater than the definedaverage particle size value. This can be identified by the term “D₅₀” or“d_((0.5))”. The average particle size can be measured using varioustechniques such as microscopy, laser diffraction, photon correlationspectroscopy (PCS) and Coulter's principle.

In the context of present invention, the “hydrocolloid” refers to acolloid system wherein hydrophilic colloid particles (e.g., hydrophilicpolymers) are dispersed in water. The hydrocolloid system can exist ingel state or sol (liquid) state. In suspension compositions, thehydrocolloids function as thickening, stabilizing and suspending agents.Non-limiting examples of hydrocolloid include xanthan gum, gum arabic,guar gum, locust bean gum, alginate, starch, agar-agar, carrageenan,gelatin, Avicel RC591® (mixture of microcrystalline cellulose & sodiumcarboxymethyl cellulose) and cellulose derivatives (e.g., carboxymethylcellulose sodium). Preferably, the hydrocolloid includes xanthan gum orcarboxymethylcellulose sodium.

As used herein, the term “container” refers to single unit-dosecontainer or multi-dose container. Suitable single unit-dose containersor multi-dose containers include, but are not limited to, glass,aluminum, polypropylene or high density polyethylene, for example, highdensity polyethylene containers produced using a blow-fill-sealmanufacturing technique. In one embodiment, the container is a sprayerwhich delivers the pharmaceutical composition in the form of a finemist. A sprayer generally includes a container containing apharmaceutical composition, a pump sealed (e.g., hermetically engaged)with the container, an actuator removably receiving a top portion of thepump, and a cap removably engaged with the container and the actuator.

The present invention relates to a stable fixed dose, aqueouspharmaceutical composition (e.g., contained in a container) for nasaladministration to a human, where the composition comprises about 0.001%w/w to about 0.075% w/w mometasone or its salt and about 0.5% w/w toabout 0.8% w/w olopatadine or its salt.

The pharmaceutical composition may be in the form of a solution or asuspension, but preferably the composition is in the form of asuspension (more preferably, a single phase suspension), whereinmometasone or its salt is present in particle form and olopatadine orits salt is present in dissolved form. The mometasone or its salt andolopatadine or its salt may be present at a weight ratio of about 1:3 toabout 1:106, or from about 1:5 to about 1:53 or preferably from about1:5 to about 1:36.

The composition preferably also includes a hydrocolloid. In oneembodiment, the composition is a suspension and includes a hydrocolloidin a sufficient amount to prevent phase separation (i.e., separation ofthe particles and solution) after 3 or 6 months of storage at 25±2° C.and 60%±5% relative humidity (RH) or at 40±2° C. and 75%±5% RH. In oneembodiment, the aqueous pharmaceutical composition is a single phasesuspension which remains a single phase suspension even after 3 or 6months of storage at 25±2° C. and 60%±5% RH or at 40±2° C. and 75%±5%RH.

The term ‘stable’ as used in connection with aqueous suspensions refersto a composition when shaken and then stored for at least 24 hours atambient condition does not show phase separation on visual inspection.Preferably, such stable composition does not show phase separation for aperiod of at least 3 days, or at least 5 days, or at least 7 days. Inone aspect, the ‘stable’ composition of the present invention shows,upon shaking (e.g., for 1 minute) and visual inspection, no lumpformation and a total impurity content of no more than 1.0% afterstorage at ambient conditions (at about 25° C. and a relative humidityof about 60%) for a period of at least 6 months.

In the context of the present invention, the drug content and impuritiescan be determined by various analytical techniques such as HPLC, LC-MS,TLC and the like.

It was observed that when various pharmaceutical compositions for nasaladministration comprising mometasone or its salt and olopatadine or itssalt were prepared, the compositions generally showed physicalseparation in the suspension composition. This physical instabilityfurther leads to lack of dose uniformity. Surprisingly, it was foundthat addition of a hydrocolloid at certain concentrations (e.g. at aconcentration of at least about 0.1% w/w) in the suspension compositionyielded a physically stable composition (with no separation) suitablefor nasal administration.

Another embodiment is a stable fixed dose, aqueous pharmaceuticalsuspension composition (e.g., contained in a container) for nasaladministration to a human, where the composition comprises about 0.025%w/w to about 0.05% w/w mometasone or its salt, about 0.6% w/w to about0.7% w/w olopatadine or its salt and a hydrocolloid.

Yet another embodiment is a stable fixed dose, aqueous pharmaceuticalsuspension composition (e.g., contained in a container) for nasaladministration to a human, where the composition comprises about 0.025%w/w to about 0.05% w/w mometasone or its salt, about 0.6% w/w to about0.7% w/w olopatadine or its salt and a hydrocolloid which includescarboxymethylcellulose sodium and xanthan gum. The hydrocolloid may bepresent at a concentration of at least about 0.1% w/w of thecomposition.

Yet another embodiment is a stable fixed dose, aqueous pharmaceuticalsuspension composition (e.g., contained in a container) for nasaladministration to a human, comprising about 0.025% w/w to about 0.05%w/w mometasone furoate, about 0.6% w/w to about 0.7% w/w olopatadinehydrochloride and a hydrocolloid which comprises xanthan gum. Thexanthan gum may be present at a concentration of at least about 0.1%w/w, or preferably between about 0.3% w/w to about 3% w/w of thecomposition.

Yet another embodiment is a stable fixed dose, aqueous pharmaceuticalsuspension composition (e.g., contained in a container) for nasaladministration to a human, comprising about 0.025% w/w to about 0.05%w/w mometasone furoate, about 0.6% w/w to about 0.7% w/w olopatadinehydrochloride and a hydrocolloid which comprises sodium carboxymethylcellulose. The sodium carboxymethyl cellulose may be present at aconcentration of at least about 0.1% w/w, or preferably between about0.1% w/w to about 3% w/w of the composition.

Yet another embodiment is a stable fixed dose aqueous pharmaceuticalcomposition in the form of suspension (e.g., contained in a container)for nasal administration to a human, comprising mometasone or itspharmaceutically acceptable salt, olopatadine or its pharmaceuticallyacceptable salt, a hydrocolloid (e.g., at a concentration of at leastabout 0.1% w/w of the composition) and a pharmaceutical acceptableexcipient.

It will also be appreciated to the skilled artisan that in order toimprove the physical properties, appearances, or smells of thecomposition of the present invention, one or more furtherpharmaceutically acceptable excipients may be added as desired. Suitablepharmaceutical acceptable excipients include, but are not limited to,chelating agents, preservatives, buffers, surfactants, isotonicityagents, taste masking agents, antioxidants, humectants, pH adjustingagents, and any combination of any of the foregoing.

Suitable surfactants which can be used for preparing aqueous nasal spraycomposition may include one or more of anionic, cationic, non-ionic orzwitterionic surfactants.

Examples of suitable surfactants which can be employed in the aqueousnasal spray suspension may be selected from, but not limited to,polyethoxylated sorbitan derivatives such as polysorbates, their etherethoxylates, produced by reaction of sorbitan esters with ethyleneoxide, polyoxyethylene alkyl phenol, polyoxyethylene cetyl ether,polyoxyethylene alkyl-aryl ether, polyoxyethylene monolaurate,polyoxyethylene vegetable oil, polyoxyethylene sorbitan monolaurate,polyoxyethylene esters or mixed fatty and resin acids, polyoxyethylenesorbitol lanolin derivative, polyoxyethylene tridecylether,polyoxyethylene sorbitan esters of mixed fatty and resin acids,polyoxyethylene sorbitan monostearate, polyoxyethylene sorbitanmonooleate, polyoxyethylene monostearate, polyoxyethylene stearyl ether,polyoxyethylene oleyl ether, polyoxyethylene tridecyl ether,polyoxyethylene fatty alcohol, polyoxyethylene alkyl amine,polyoxyethylene glycol monopalmitate, polyoxyethylene sorbitanmonopalmitate, polyoxyethylene cetyl ether, polyoxyethylene oxypropylenestearate, polyoxyethylene lauryl ether, polyoxyethylene lanolinderivative, sodium oleate, quaternary ammonium derivative, potassiumoleate, N-cetyl N-ethyl morpholinium ethosulfate, sodium lauryl sulfateor mixtures thereof. Preferred surfactants are polyethoxylated sorbitanderivatives (such as polysorbate 80). The amount of surfactant may rangefrom about 0.001% to about 1% w/w relative to the total weight of thecomposition.

In order to improve the ability of the aqueous nasal spray suspension tobe tolerated on administration to the nasal mucous membrane, it isadvantageous to formulate it as isotonic. The osmolality can be set byvariation of the amounts of the substances present in the aqueous nasalspray suspension besides mometasone, olopatadine and any furthersubstances present, and/or by addition of an isotonicity agent,preferably a physiologically tolerated salt, such as, for example,sodium chloride or potassium chloride, or a physiologically toleratedpolyol, such as, for example, a sugar alcohol, in particular sorbitol orglycerol, in the concentration necessary for rendering isotonic.

Examples of suitable preservatives which can be employed in the aqueousnasal spray suspension include, but are not limited to, benzyl alcohol,quaternary ammonium halides, phenylcarbinol, thimerosal, and disodiumedetate. Quaternary ammonium halide preservatives are preferred.Suitable quaternary ammonium halide preservatives includepolyquaternium-1 and benzalkonium halides. Preferred benzalkoniumhalides include benzalkonium chloride and benzalkonium bromide. Theamount of the preservative present in the aqueous nasal spray suspensionmay range from about 0.005 to about 0.2% w/w relative to the totalweight of the composition. Preferably, the preservative is present at aconcentration of about 0.02% w/w relative to the total weight of thecomposition.

Examples of suitable chelating agents which can be employed in theaqueous nasal spray suspension include, but are not limited to, edetatedisodium (EDTA), edetate trisodium, edetate tetrasodium, anddiethyleneamine pentaacetate, preferably EDTA. The amount of thechelating agent present in the aqueous nasal spray suspension of thepresent invention may range from about 0.0002 to about 0.5% w/w relativeto the total weight of the composition.

Examples of suitable buffers which can be employed in the aqueous nasalspray suspension include, but are not limited to, citric acid, aceticacid, fumaric acid, hydrochloric acid, malic acid, nitric acid,phosphoric acid, propionic acid, sulfuric acid, tartaric acid, phosphatesalts (e.g., dibasic sodium phosphate, such as dibasic sodium phosphateheptahydrate), or combinations thereof. The suspension of the presentinvention may comprise an amount of a buffer sufficient to maintain thepH of the composition to from about 3 to about 6. Preferably, the amountof buffer ranges from about 0.005% to about 1% w/w relative to the totalweight of the composition.

Examples of suitable sweetener/taste masking agents which can beemployed in the aqueous nasal spray suspension include, but are notlimited to, sucralose, thaumatin (e.g., Talin^((R))), sucrose, saccharin(including salt forms such as sodium and calcium salts), fructose,glucose, dextrose, corn syrup, aspartame, acesulfame-K, xylitol,sorbitol, erythritol, ammonium glycyrrhizinate, neotame, mannitol,eucalyptus oil, camphor, and natural or artificial flavors or flavoringagents (for example menthol, mints, vanilla, orange, etc.), orcombinations of two or more of such agents. A particularly preferredtaste masking agent is sucralose. The amount of the sweetener/tastemasking agent present in the aqueous nasal spray suspension may rangefrom about 0.01% to about 1% w/w relative to the total weight of thecomposition.

Examples of suitable antioxidants which can be employed in the aqueousnasal spray suspension include, but are not limited to, ascorbic acid,alpha-tocopherol (vitamin-E), butylated hydroxyanisole, butylatedhydroxytoluene, glutathione, and any combination of any of theforegoing. The amount of the antioxidants present in the aqueous nasalspray composition may range from about 0.0002% to about 0.5% w/wrelative to the total weight of the composition.

Examples of suitable humectants which can be employed in the aqueousnasal spray suspension include, but are not limited to, glycerin,sorbitol, polyethylene glycol, propylene glycol or mixtures thereof,which are mixed with a suitable humectant vehicle such as water. Theamount of humectant present in the aqueous nasal spray suspension mayrange from about 0.0002% to about 0.5% w/w relative to the total weightof the composition.

Suitable pH adjusting agents include, but are not limited to, sodiumhydroxide and hydrochloric acid.

In the context of present invention, the pharmaceutical stable fixeddose suspension composition for nasal administration may have a pH ofbetween about 3.3 and about 4.1, or between about 3.5 and about 3.9. Theinventors discovered that the olopatadine hydrochloride crystallizes outof the fixed dose combination aqueous suspension at a pH of 5 to 5.5.The olopatadine hydrochloride, however, remains dissolved in the aqueoussuspension at a pH of about 3.3 to about 4.1.

The aqueous pharmaceutical composition preferably is substantially freeof crystals of olopatadine hydrochloride. In one embodiment, the aqueouspharmaceutical composition contains less than 2%, less than 1%, lessthan 0.5%, less than 0.2%, or less than 0.1% of crystalline olopatadinehydrochloride, based on the 100% total weight of olopatadinehydrochloride in the composition. In another embodiment, the aqueouspharmaceutical composition is substantially free of crystals ofolopatadine hydrochloride after 3 or 6 months of storage at 25±2° C. and60%±5% RH or at 40±2° C. and 75%±5% RH. In yet another embodiment, theaqueous pharmaceutical composition contains less than 2%, less than 1%,less than 0.5%, less than 0.2%, or less than 0.1% of crystallineolopatadine hydrochloride, based on the 100% total weight of olopatadinehydrochloride in the composition, after 3 or 6 months of storage at25±2° C. and 60%±5% RH or at 40±2° C. and 75%±5% RH.

The osmolality of the composition may range between about 200 mOsm/kgand about 400 mOsm/kg, or about 250 mOsm/kg and about 350 mOsm/kg. Theviscosity of the composition may be about 10 cps to about 200 cps orpreferably from about 20 cps to about 150 cps.

In yet another aspect, the pharmaceutical composition in the form ofsuspension and contains mometasone furoate in particles having meanparticle size in the range of from about 1 μm to about 20 μm, orpreferably from about 1 μm to about 15 μm. In an aspect, the suspensionpharmaceutical composition of the present invention has mean particlesize of less than 15 μm when determined by microscopy technique.

In yet another aspect, the pharmaceutical composition, when delivered asa nasal spray has a spray pattern having a longest axis of about 15-75mm, a shortest axis of about 10-65 mm, and an ellipticity of about 1-2.

In the context of present invention, the viscosity can be determined byvarious known instruments such as a Dynamic stress rheometer orBrookfield viscometer. In a preferred embodiment, the viscosity isdetermined by a Brookfield viscometer by measuring torque transmissionthrough a sample using a rotating spindle.

In another embodiment, the present invention relates to a stable fixeddose, aqueous pharmaceutical composition (e.g., contained in acontainer) for nasal administration to a human, where the compositioncomprises about 0.001% w/w to about 0.075 w/w mometasone furoatemonohydrate and about 0.5 w/w to about 0.8% w/w olopatadinehydrochloride.

Another embodiment is a stable fixed dose pharmaceutical composition inthe form of suspension (e.g., contained in a container) for nasaladministration to a human, comprising mometasone furoate monohydrate,olopatadine hydrochloride and a hydrocolloid which comprises xanthan gumat a concentration of about 0.3% w/w of the composition, wherein thecomposition has a pH between about 3.5 and about 3.9.

Yet another embodiment is a stable fixed dose pharmaceutical compositionin the form of suspension (e.g., contained in a container) for nasaladministration to a human, comprising mometasone furoate monohydrate,olopatadine hydrochloride and a hydrocolloid which comprises sodiumcarboxymethyl cellulose at a concentration of about 0.5% w/w of thecomposition, wherein the composition has a pH between about 3.5 andabout 3.9.

Yet another embodiment is a stable fixed dose pharmaceutical aqueoussuspension composition (e.g., contained in a container) for nasaladministration to a human, where the composition comprises (1) about0.025% w/w mometasone furoate monohydrate, (2) about 0.665% w/wolopatadine hydrochloride, (3) a hydrocolloid selected from about 0.3%w/w of xanthan gum and about 0.5 w/w carboxymethyl cellulose sodium, (4)about 0.02% w/w benzalkonium chloride, (5) about 0.4% w/w sodiumchloride, (6) about 0.01% w/w di-sodium edetate, (7) about 0.94% w/wsodium phosphate heptahydrate, and (8) about 0.01% w/w polysorbate 80.

Yet another embodiment is a stable fixed dose pharmaceutical aqueoussuspension composition (e.g., contained in a container) for nasaladministration to a human, where the composition comprises (1) about0.050% w/w mometasone furoate monohydrate, (2) about 0.665% w/wolopatadine hydrochloride, (3) a hydrocolloid selected from about 0.3%w/w of xanthan gum and about 0.5 w/w carboxymethyl cellulose sodium, (4)about 0.02% w/w benzalkonium chloride, (5) about 0.4% w/w sodiumchloride, (6) about 0.01% w/w di-sodium edetate, (7) about 0.94% w/wsodium phosphate heptahydrate, and (8) about 0.01% w/w polysorbate 80.

Yet another embodiment is a stable fixed dose pharmaceutical aqueoussuspension composition (e.g., contained in a container) for nasaladministration to a human, where the composition comprises (1) about0.025% w/w mometasone furoate monohydrate, (2) about 0.665% w/wolopatadine hydrochloride, (3) a hydrocolloid selected from about 0.3%w/w of xanthan gum and about 0.5 w/w carboxymethyl cellulose sodium, (4)about 1% w/w to about 1.2% w/w mixture of microcrystalline cellulose andcarboxymethyl cellulose sodium, (5) about 0.02% w/w benzalkoniumchloride, (6) about 0.4% w/w sodium chloride, (7) about 0.01% w/wdi-sodium edetate, (8) about 0.94% w/w sodium phosphate heptahydrate,and (9) about 0.01% w/w polysorbate 80.

Yet another embodiment is a stable fixed dose pharmaceutical aqueoussuspension composition (e.g., contained in a container) for nasaladministration to a human, where the composition comprises (1) about0.050% w/w mometasone furoate monohydrate, (2) about 0.665% w/wolopatadine hydrochloride, (3) a hydrocolloid selected from about 0.3%w/w of xanthan gum and about 0.5 w/w carboxymethyl cellulose sodium, (4)about 1% w/w to about 1.2% w/w mixture of microcrystalline cellulose andcarboxymethyl cellulose sodium, (5) about 0.02% w/w benzalkoniumchloride, (6) about 0.4% w/w sodium chloride, (7) about 0.01% w/wdi-sodium edetate, (8) about 0.94% w/w sodium phosphate heptahydrate,and (9) about 0.01% w/w polysorbate 80.

Yet another embodiment is a stable suspension suitable for nasaladministration to a human, comprising (a) an aqueous solvent, (b)particles of mometasone furoate suspended in the solvent, the particleshaving a mean particle size of from about 1 to about 20 μm, (c)olopatadine hydrochloride dissolved in the solvent, and (d) ahydrocolloid, the suspension having a viscosity in the range of about 20cps to about 150 cps. In one preferred embodiment, the suspension has apH of about 3.5-3.9, and osmolality in the range of about 250 mOsm/kg toabout 350 mOsm/kg. In one embodiment, the suspension further comprises achelating agent, a preservative, a buffer, a surfactant, an isotonicityagent, and optionally a pH adjusting agent.

Preferably, the suspensions of the present invention have only one phase(i.e., they are preferably a single phase suspension).

In a further embodiment, the present invention relates to kit comprisinga stable fixed dose, aqueous pharmaceutical composition of the presentinvention contained in a container for nasal administration and apackage insert containing instructions about the use of saidpharmaceutical composition. In one preferred embodiment, the containeris part of a sprayer which has an actuator. When the actuator isactuated, the composition is delivered in the form of a spray.

In a further embodiment, the pharmaceutical composition is contained ina sprayer, and has, on deliver a spray of the composition to a humannose, a spray pattern having a longest axis of 15-75 mm, a shortest axisof 10-65 mm, and an ellipticity of 1-2.

In the context of present invention, the pharmaceutical composition whendelivered as a nasal spray using a sprayer yields a specific spraypattern and spray droplet size. The spray pattern can be determined byvarious known techniques such as with an ADSA with NSPUA set up (InnovaSystem) and the spray droplet size distribution can be determined byvarious known techniques such as with a Malvern Spraytec with NSPUA setup (Innova System).

The following describes a typical procedure for characterizing dropletsize distribution of the spray—The sprayer is loaded with a compositionas described above and primed by an actuating pump via an actuator untila fine mist appears out of the nozzle of the sprayer. A commerciallyavailable laser diffraction instrument is arranged so that the nozzle isabout 3 cm or 6 cm below the laser beam of the laser diffractioninstrument. The pump is actuated with a conventional mechanical actuatorusing a constant force. The resulting spray of the composition crossesthe laser beam. Data are collected for D₁₀, D₅₀, D₉₀, SPAN, and % Volume<10 μm. The average values for each of these parameters for three spraysare calculated.

One embodiment is a stable fixed dose, aqueous pharmaceuticalcomposition comprising mometasone furoate monohydrate, olopatadinehydrochloride and optionally a hydrocolloid contained in a sprayer,wherein each spray of the aqueous pharmaceutical composition provides(i) mometasone furoate monohydrate equivalent to about 50 mcg ofmometasone furoate and (ii) olopatadine hydrochloride equivalent toabout 600 mcg olopatadine.

Another embodiment is a method for treating rhinitis, or foradministering mometasone and olopatadine. The method includes spraying astable fixed dose, aqueous pharmaceutical composition comprisingmometasone furoate monohydrate, olopatadine hydrochloride and optionallya hydrocolloid such that each spray of the aqueous pharmaceuticalcomposition provides (i) mometasone furoate monohydrate equivalent toabout 50 mcg of mometasone furoate and (ii) olopatadine hydrochlorideequivalent to about 600 mcg olopatadine.

Yet another embodiment is a stable fixed dose, aqueous pharmaceuticalcomposition comprising mometasone furoate monohydrate, olopatadinehydrochloride and optionally a hydrocolloid contained in a sprayer,wherein each spray of the aqueous pharmaceutical composition provides(i) mometasone furoate monohydrate equivalent to about 25 mcg ofmometasone furoate and (ii) olopatadine hydrochloride equivalent toabout 600 mcg olopatadine.

Yet another embodiment is a method for treating rhinitis, or foradministering mometasone and olopatadine. The method includes spraying astable fixed dose, aqueous pharmaceutical composition comprisingmometasone furoate monohydrate, olopatadine hydrochloride and optionallya hydrocolloid such that each spray of the aqueous pharmaceuticalcomposition provides (i) mometasone furoate monohydrate equivalent toabout 25 mcg of mometasone furoate and (ii) olopatadine hydrochlorideequivalent to about 600 mcg olopatadine.

The stable aqueous nasal spray suspension of mometasone and olopatadinemay comprise one or more additional pharmaceutical active agent/sselected from the therapeutic category of, but not limited to,non-steroidal anti-inflammatory agents, decongestants, and anycombination of any of the foregoing.

The aqueous nasal spray suspension can be administered as a drop or anyother form suitable for topical administration. The composition may alsobe administered using a nasal tampon or a nasal sponge.

In a preferred embodiment, the aqueous suspension is provided in theform of nasal spray wherein the suspension is administered in a singleunit-dose container or multi-dose container. Suitable single unit-dosecontainers or multi-dose containers include, but are not limited to,glass, aluminum, polypropylene or high density polyethylene, forexample, high density polyethylene containers produced using ablow-fill-seal manufacturing technique.

In certain additional embodiments, the invention provides a multi dosagecomposition of matter, comprising: (a) a multi-unit dosage of apharmaceutical composition of the present invention; and (b) a containercomprising: (i) a squeezable chamber holding the multi dosage of thecomposition and having an opening wherein the dosage exits the openingwhen the squeezable chamber is squeezed; and (ii) a closure mechanismremovably attached to the opening of the squeezable chamber. In certainembodiments, the multi dosage container is made of a moldable polymer.

In such embodiments, suitable polymers include, but are not limited to,polyethylene, polypropylene (PP), polystyrene (PS), nylon (Ny),polyvinyl chloride (PVC), polyethylene terephthalate (PET),polycarbonate (PC), polyoxymethylene (POM), polysulfon (PSF),polyethersulfon (PES), polyacrylate (PAR), and polyamid (PA). In certainembodiments, polymers include polyethylene, particularly medium-densitypolyethylene (MDPE) (or branched polyethylene) or high densitypolyethylene (HDPE) (or linear, polyethylene). In one embodiment, themulti dose container is made of high density polyethylene (HDPE).

Other means for delivering the nasal spray, such as inhalation via ametered dose inhaler (MDI), may also be used. Several types of MDIs areregularly used for administration by inhalation. These types of devicescan include breath-actuated MDIs, spacer/holding chambers in combinationwith MDIs, and nebulizers. The term “MDI” as used herein refers to aninhalation delivery system comprising, for example, a canistercontaining a mixture of an active agent and a propellant optionally withone or more excipients, a metered dose valve, an actuator, and amouthpiece. The canister is usually filled with a suspension of anactive agent, such as the nasal spray composition, and a propellant,such as one or more hydrofluoroalkanes [e.g. 1,1,1,2-tetrafluoroethane(HFA-134a) and 1,1,1,2,3,3,3-heptafluoropropane (HFA-227)],chlorofluorocarbons, and alcohols such as ethanol, isopropanol, butanol,propanol or mixtures thereof. When the actuator is depressed a metereddose of the suspension is aerosolized for inhalation. Particlescomprising the active agent are propelled towards the mouthpiece wherethey may then be inhaled by a subject.

The present invention also relates to a method of treating rhinitis in ahuman in need thereof comprising administering by the nasal route astable fixed dose, aqueous pharmaceutical composition of the presentinvention. For example, the pharmaceutical composition which may becontained in a container comprises about 0.025 w/w to about 0.05% w/wmometasone or its salt and about 0.5% w/w to about 0.8% w/w olopatadineor its salt.

In a further embodiment, the present invention relates to use of about0.025% w/w to about 0.05% w/w mometasone or its salt and about 0.5% w/wto about 0.8% w/w olopatadine or its salt in the preparation of a stablefixed dose, aqueous pharmaceutical composition (e.g., contained in acontainer) for the treatment of rhinitis in a human in need thereof. Anypharmaceutical composition described herein may be used.

In a further embodiment, the present invention relates to a stable fixeddose, aqueous pharmaceutical composition (e.g., contained in acontainer) for nasal administration comprising about 0.025 w/w to about0.05 w/w mometasone or its salt and about 0.5% w/w to about 0.8% w/wolopatadine or its salt for the treatment of rhinitis in a human in needthereof.

Rhinitis in the context of present invention includes, but is notlimited to, irritation and inflammation of the mucous membrane insidethe nose and nasal and non-nasal symptoms associated therewith. Itincludes allergic rhinitis, persistent rhinitis, perennial rhinitis,seasonal rhinitis, chronic rhinitis, rhinitis medicamentosa, vasomotorrhinitis, infective rhinitis, autonomic rhinitis, hormonal rhinitis,drug-induced rhinitis, atrophic rhinitis, and gustatory rhinitis.Preferably, it includes allergic rhinitis, perennial rhinitis,persistent rhinitis, seasonal rhinitis and nasal and non-nasal symptomsassociated therewith.

In the context of present invention, the nasal and non-nasal symptomsassociated with allergic rhinitis include sneezing, nasal itching,rhinorrhea (runny nose), nasal obstruction, coughing, ocular pruritis,excess lacrimation, headache, fatigue, common cold (also known asnasopharyngitis, rhinopharyngitis, acute coryza, or cold), malaise andcognitive impairment.

It will be understood that various modifications may be made to theembodiments disclosed herein. Therefore the above description should notbe construed as limiting, but merely as exemplifications of preferredembodiments. Other arrangements and methods may be implemented by thoseskilled in the art without departing from the scope and spirit of thisinvention.

The following examples are provided to enable one skilled in the art topractice the invention and are merely illustrative of the invention. Theexamples should not be read as limiting the scope of the invention.

EXAMPLES Examples 1-2 Suspension Compositions Containing MometasoneFuroate, Olopatadine HCl and Carboxymethylcellulose Sodium

Example 1 Example 2 SN Ingredient (% w/w) (% w/w) 1 Mometasone Furoatemonohydrate 0.050 0.025 Eq. to Mometasone furoate 2 OlopatadineHydrochloride 0.665 0.665 3 Avicel RC 591 (Microcrystalline Cellulose1.200 1.200 and Carboxymethylcellulose Sodium) 4 Benzalkonium chloride(50% solution) 0.040 0.040 5 Carboxymethylcellulose Sodium 0.500 0.500(Cekol 2000 P) 6 Sodium chloride 0.410 0.410 7 Edetate disodium 0.0100.010 8 Dibasic sodium phosphate heptahydrate 0.940 0.940 9 Polysorbate80 0.010 0.010 10 Sodium Hydroxide Q.S. Q.S. 11 Hydrochloric acid Q.S.Q.S. 12 Water for injection Q.S. Q.S. Observations Physical observationon standing for 24 No phase No phase hours separation separationobserved observed Mean Particle size by microscopy Below Below 15 μm. 15μm.Manufacturing Procedure:

-   -   1. Avicel RC-591 was added in water for injection with        homogenization and allowed to hydrate.    -   2. Carboxymethylcellulose Sodium was dispersed in water for        injection and added to step-1.    -   3. Dibasic sodium phosphate heptahydrate, Sodium chloride,        Edetate disodium and Olopatadine were dissolved in water. The pH        was adjusted to 2.8-3.2 with Hydrochloric acid.    -   4. Step-3 was added to Step-1 with homogenization.    -   5. Polysorbate 80 was dissolved in water for injection.        Mometasone Furoate monohydrate was added and stirred to form        slurry.    -   6. Step-5 was added to Step-4 with homogenization.    -   7. Benzalkonium chloride was dissolved in water for injection.    -   8. Step-7 was added to Step-6 with homogenization.    -   9. The pH was checked and adjusted to 3.5-3.9 with HCl and the        total weight was adjusted with Water for injection. The        osmolality of the composition was about 250-350 mOsm/kg.        The composition was subjected to stability studies at different        conditions. The results of the same are as follows:        Container details: Sprayer containing HDPE bottle crimped with        pump and fitted with an actuator and cap.

Stability Study Data Initial 3 months 6 months Test Ex. 1 Ex. 2 Ex. 1Ex. 2 Ex. 1 Ex. 2 Stability condition (25° C. ± 2° C. & 60% RH ± 5% RH)pH 3.61 3.69 3.73 3.78 3.81 Osmolality (mOsm)* 310 308 299 298 302 311Viscosity (cps)** 32.5 42.5 42.3 40.6 40.9 Weight per ml (g/ml) 1.011.021 1.024 1.029 1.019 Assay of mometasone furoate (% w/w) 101 102.499.1 99.3 98.2 97.2 Assay of olopatadine 98.2 99.9 97.3 99.1 97.8 97.9hydrochloride (% w/w) Related substances for mometasone furoate ImpurityDMCF (%) 0.02 0.03 0.09 0.10 0.14 0.17 Any other impurity (%) 0.04 0.040.03 Total impurities (%) 0.09 0.23 0.29 0.31 0.34 Related substancesfor olopatadine hydrochloride Olopatadine E-isomer (%) 0.08 0.07 0.090.09 Any other impurity (%) 0.03 0.04 0.09 0.12 0.11 0.11 Totalimpurities (%) 0.15 0.16 0.20 0.25 0.37 0.38 Spray Pattern (at 6 cm)Major Axis (mm) 52 60 63 59 61 Minor Axis (mm) 43 47 49 53 49 51Ellipticity 1.2 1.1 1.2 1.2 1.2 1.2 Droplet size distribution (at 6 cm)D₁₀ (μm) 18.91 19.45 19.26 19.70 19.33 18.88 D₅₀ (μm) 36.39 37.61 35.9637.34 39.28 37.85 D₉₀ (μm) 72.46 76.44 70.29 75.78 85.42 72.07 SPAN 1.471.51 1.42 1.5 1.67 1.46 Stability condition (40° C. ± 2° C. & 75% RH ±5% RH) pH 3.61 3.68 3.72 3.59 3.68 Osmolality (mOsm) 310 308 298 306 305299 Viscosity (cps) 32.5 45.2 42.6 41.8 41.5 Weight per ml (g/ml) 1.011.023 1.019 1.026 1.025 Assay of mometasone furoate (%) 101 102.4 99.8100.4 98.3 98.4 Assay of olopatadine 98.2 99.9 99.3 102.5 98.7 99.7hydrochloride (%) Related substances for mometasone furoate ImpurityDMCF (%) 0.02 0.03 0.14 0.20 0.25 0.25 Any other impurity (%) 0.04 0.040.04 0.03 0.03 0.04 Total impurities (%) 0.09 0.25 0.39 0.40 0.46Related substances for olopatadine hydrochloride Olopatadine E-isomer(%) 0.08 0.07 0.08 0.08 0.09 Any other impurity (%) 0.03 0.04 0.21 0.180.31 0.30 Total impurities (%) 0.15 0.16 0.32 0.36 0.68 0.64 SprayPattern (at 6 cm) Major Axis (mm) 52 52 61 58 58 58 Minor Axis (mm) 4347 50 49 48 49 Ellipticity 1.2 1.1 1.2 1.2 1.2 1.2 Droplet sizedistribution (at 6 cm) D₁₀ (μm) 18.91 19.45 19.49 19.27 18.05 18.09 D₅₀(μm) 36.39 37.61 35.29 34.68 36.19 36.12 D₉₀ (μm) 72.46 76.44 64.6663.49 71.89 70.06 SPAN 1.47 1.51 1.28 1.27 1.50 1.44 *Determined byAdvanced Instruments Osmometer (Model 3250). **Determined by Brookfieldviscometer.

Examples 3-4 Suspension Compositions Containing Mometasone Furoate,Olopatadine HCl and Xanthan Gum

Example 3 Example 4 SN Ingredient (% w/w) (% w/w) 1 Mometasone Furoatemonohydrate 0.050 0.025 Eq. to Mometasone furoate 2 Olopatadine HCl0.665 0.665 3 Avicel RC 591 (Microcrystalline Cellulose 1.000 1.000 andCarboxymethylcellulose Sodium) 4 Benzalkonium chloride (50% solution)0.040 0.040 5 Xantural 75 (Xanthan Gum) 0.300 0.300 6 Sodium chloride0.410 0.410 7 Edetate disodium 0.010 0.010 8 Dibasic sodium phosphateheptahydrate 0.940 0.940 9 Polysorbate 80 0.010 0.010 10 SodiumHydroxide Q.S. Q.S. 11 Hydrochloric acid Q.S. Q.S. 12 Water forinjection Q.S. Q.S. Observations Physical observation on standing for 24hours No phase No phase separation separation observed observed MeanParticle size by microscopy Below Below 15 μm. 15 μm.Manufacturing Procedure:

-   -   1. Avicel RC-591 was added in Water for injection with        homogenization and allowed to hydrate.    -   2. Xanthan gum was dispersed in Water for injection and added to        step-1.    -   3. Dibasic sodium phosphate heptahydrate, Sodium chloride,        Edetate disodium and Olopatadine were dissolved in water. The pH        was adjusted to 2.8-3.2 with Hydrochloric acid.    -   4. Step-3 was added to Step-1.    -   5. Polysorbate 80 was dissolved in water for injection.        Mometasone Furoate monohydrate was added to it and stirred to        form slurry.    -   6. Step-5 was added to Step-4 with homogenization.    -   7. Benzalkonium chloride was dissolved in water for injection.    -   8. Step-7 was added to Step-6 with homogenization.    -   9. The pH was checked and adjusted to 3.5-3.9 with HCl and the        weight was adjusted with water for injection. The osmolality of        the composition was about 250-350 mOsm/kg.

The composition was subjected to stability studies at differentconditions. The results of the same are as follows:

Container details: Sprayer containing HDPE bottle crimped with pump andfitted with a actuator and cap

Stability Study Results Initial 3 months 6 months Test Ex. 3 Ex. 4 Ex. 3Ex. 4 Ex. 3 Ex. 4 Stability condition (25° C. ± 2° C. & 60% RH ± 5% RH)pH 3.65 3.67 3.78 3.65 3.70 3.62 Osmolality (mOsm) 307 312 302 316 308308 Viscosity (cps) 124.2 129.1 127.9 129.9 126.2 126.8 Weight per ml(g/ml) 1.015 1.022 1.02 1.023 1.02 1.019 Assay of mometasone furoate (%)99.9 102.8 102.2 99.0 98.7 100.4 Assay of olopatadine hydrochloride (%)99.2 100.7 99.7 99.7 99.4 99.6 Related substances for mometasone furoateImpurity DMCF (%) 0.02 0.02 0.04 0.05 0.03 0.05 Any other impurity (%)0.03 0.04 0.03 0.04 Total impurities (%) 0.11 0.10 0.15 0.16 0.12 0.16Related substances for olopatadine hydrochloride Olopatadine E-isomer(%) 0.08 0.07 0.09 0.11 0.11 0.10 Any other impurity (%) 0.03 0.04 0.050.05 0.08 0.08 Total impurities (%) 0.18 0.15 0.24 0.20 0.33 0.33 SprayPattern (at 6 cm) Major Axis (mm) 46 59 59 56 54 Minor Axis (mm) 38 4744 35 43 Ellipticity 1.2 1.3 1.4 1.6 1.3 Droplet size distribution (at 6cm) D₁₀ (μm) 21.58 21.03 20.95 20.27 18.73 18.34 D₅₀ (μm) 40.44 39.7937.86 37.93 36.66 36.16 D₉₀ (μm) 78.25 77.55 74.07 74.93 70.63 70.99SPAN 1.40 1.42 1.40 1.44 1.41 1.45 Stability condition (40° C. ± 2° C. &75% RH ± 5% RH) pH 3.65 3.67 3.70 3.77 3.78 3.65 Osmolality (mOsm) 307312 309 305 302 316 Viscosity (cps) 124.2 129.1 129.6 124.3 127.9 129.9Weight per ml (g/ml) 1.015 1.022 1.017 1.027 1.022 1.020 Assay ofmometasone furoate (%) 99.9 102.8 101.7 100.6 99.6 98.9 Assay ofoloptadine 99.2 100.7 99.9 99.4 99.7 99.9 hydrochloride (%) Relatedsubstances for mometasone furoate Impurity DMCF (%) 0.02 0.02 0.10 0.120.10 0.12 Any other impurity (%) 0.03 0.03 0.02 0.03 0.05 0.03 Totalimpurities (%) 0.11 0.10 0.20 0.22 0.18 0.21 Related substances forolopatadine hydrochloride Olopatadine E-isomer (%) 0.08 0.07 0.12 0.130.11 0.11 Any other impurity (%) 0.03 0.04 0.06 0.06 0.12 0.12 Totalimpurities (%) 0.18 0.15 0.26 0.26 0.41 0.40 Spray Pattern (at 6 cm)Major Axis (mm) 46 46 56 58 54 55 Minor Axis (mm) 38 38 45 49 34 43Ellipticity 1.2 1.2 1.3 1.2 1.6 1.3 Droplet size distribution (at 6 cm)D₁₀ (μm) 21.58 21.03 20.67 23.16 19.13 19.16 D₅₀ (μm) 40.44 39.79 38.0639.08 37.34 37.26 D₉₀ (μm) 78.25 77.55 75.63 69.37 72.36 72.49 SPAN 1.401.42 1.44 1.19 1.42 1.43

Comparative Examples A and B Suspension Composition ContainingMometasone Furoate, and Olopatadine HCl

Example (% w/w) SN Ingredient A B 1 Mometasone Furoate monohydrate 0.0500.050 Eq. to Mometasone furoate 2 Olopatadine HCl 0.665 0.665 3 AvicelRC 591 (Microcrystalline Cellulose 1.00 1.00 and Carboxymethyl celluloseSodium) 4 Benzalkonium chloride (50% solution) 0.040 0.040 5Carboxymethylcellulose Sodium 0.00 0.150 (Cekol 2000 P) 6 Sodiumchloride 0.410 0.410 7 Edetate disodium 0.010 0.010 8 Dibasic sodiumphosphate heptahydrate 0.940 0.940 9 Polysorbate 80 0.010 0.010 10Sodium Hydroxide Q.S. Q.S. 11 Hydrochloric acid Q.S. Q.S. 12 Water forinjection Q.S. Q.S. Observations pH 3.7 3.7 Physical observation onstanding for 24 hours Phase Phase separation separation observedobservedManufacturing Procedure:

The manufacturing procedure as mentioned in Example 1 was followed.

Comparative Examples C and D Suspension Composition ContainingMometasone Furoate and Olopatadine HCl

Example (% w/w) SN Ingredient C D 1 Mometasone Furoate monohydrate 0.0500.050 Eq. to Mometasone furoate 2 Olopatadine HCl 0.665 0.665 3 AvicelRC 591 (Microcrystalline Cellulose 1.000 1.000 and Carboxymethylcellulose Sodium) 4 Benzalkonium chloride (50% solution) 0.040 0.040 5Xantural 75 (Xanthan Gum) 0.00 0.20 6 Sodium chloride 0.410 0.410 7Edetate disodium 0.010 0.010 8 Dibasic sodium phosphate heptahydrate0.940 0.940 9 Polysorbate 80 0.010 0.010 10 Sodium Hydroxide Q.S. Q.S.11 Hydrochloric acid Q.S. Q.S. 12 Water for injection Q.S. Q.S.Observations pH 3.73 3.70 Physical observation on standing for 24 hoursPhase Phase separation separation observed observedManufacturing Procedure:

The manufacturing procedure as mentioned in Example 3 was followed.

Although the invention herein has been described with reference toparticular embodiments, it is to be understood that these embodimentsare merely illustrative of the principles and application of the presentinvention. It is therefore to be understood that numerous modificationsmay be made to the illustrative embodiments and that other arrangementsmay be devised without departing from the spirit and scope of thepresent invention as described.

All publications, patents, and patent applications cited in thisapplication are herein incorporated by reference to the same extent asif each individual publication, patent, or patent application wasspecifically and individually indicated to be incorporated herein byreference.

We claim:
 1. A stable fixed dose aqueous pharmaceutical composition for nasal administration to a human, the composition being a single phase suspension which comprises (a) about 0.001% w/w to about 0.075% w/w mometasone or its salt in particulate form; (b) about 0.5% w/w to about 0.8% w/w olopatadine or its salt in dissolved form; and (c) a hydrocolloid system in an amount sufficient to inhibit phase separation for at least 24 hours when stored at 25±2° C. and 60% ±5% relative humidity.
 2. The pharmaceutical composition of claim 1, wherein the mometasone or its salt and the olopatadine or its salt are present in a weight ratio of about 1:3 to about 1:106.
 3. The pharmaceutical composition of claim 1, wherein the mometasone salt is mometasone furoate and the olopatadine salt is olopatadine hydrochloride.
 4. The pharmaceutical composition of claim 1, wherein the mometasone or its salt has a mean particle size in the range of about 1 μm to about 20 μm.
 5. The pharmaceutical composition of claim 1, wherein the composition has a pH of about 3.3 to about 4.1.
 6. The pharmaceutical composition of claim 4, wherein the suspension comprises a sufficient amount of a hydrocolloid system to inhibit phase separation for at least 7 days of storage at 25±2° C. and 60%±5% relative humidity.
 7. The pharmaceutical composition of claim 1, wherein the composition has a pH of about 3.3-4.1, and an osmolality in the range of about 200 mOsm/kg to about 400mOsm/kg.
 8. The pharmaceutical composition of claim 1, wherein the composition has a viscosity in the range of about 20 cps to about 150 cps.
 9. A stable fixed dose pharmaceutical composition for nasal administration to a human, said composition is a single phase aqueous suspension comprising (1) about 0.025% w/w to about 0.05% w/w mometasone or its salt in particulate form, (2) about 0.6% w/w to about 0.7% w/w olopatadine or its salt in dissolved form, and (3) a hydrocolloid system in an amount sufficient to inhibit phase separation for at least 24 hours when stored at 25±2° C. and 60%±5% relative humidity.
 10. The pharmaceutical composition of claim 9, wherein the composition comprises about 0.025% w/w mometasone furoate.
 11. The pharmaceutical composition of claim 9, wherein the composition comprises about 0.05% w/w mometasone furoate.
 12. The pharmaceutical composition of claim 9, wherein the composition comprises about 0.665% w/w olopatadine hydrochloride.
 13. The pharmaceutical composition of claim 9, wherein the composition further comprises a pharmaceutically acceptable excipient selected from the group consisting of chelating agents, preservatives, buffers, surfactants, isotonicity agent, and any combination of any of the foregoing.
 14. The pharmaceutical composition of claim 9, wherein the composition has a pH of about 3.5-3.9, and an osmolality in the range of about 250 mOsm/kg to about 350mOsm/kg.
 15. The pharmaceutical composition of claim 9, wherein the composition has a viscosity in the range of about 20 cps to about 150 cps.
 16. The pharmaceutical composition of claim 9, wherein the composition has a viscosity in the range of about 20 cps to about 150 cps and is contained in a container, and when delivered as a nasal spray has a spray pattern having a longest axis of 15-75 mm, a shortest axis of 10-65 mm, and an ellipticity of 1-2.
 17. A method of treating rhinitis in a human in need thereof comprising administering by the nasal route to the human the pharmaceutical composition of claim
 1. 18. The pharmaceutical composition of claim 9, wherein the composition has a pH of 3.3 to 4.1.
 19. A stable fixed dose pharmaceutical composition for nasal administration to a human, the composition being a single phase aqueous suspension comprising: 0.025% or 0.05% w/w mometasone furoate monohydrate; 0.665% w/w olopatadine hydrochloride; 0.5% w/w carboxymethyl cellulose sodium; 1.2% w/w of a mixture of microcrystalline cellulose and carboxymethyl cellulose sodium; 0.02% w/w benzalkonium chloride; 0.41% w/w sodium chloride; 0.01% w/w di-sodium edetate; 0.94% w/w sodium phosphate heptahydrate; and 0.01% w/w polysorbate 80; wherein the composition has a pH of about 3.3 to about 4.1.
 20. The pharmaceutical composition of claim 19, wherein the composition has an osmolality of 250 mOsm/kg to 350 mOsm/kg, a viscosity of 20 cps to 150 cps, and the mometasone furoate monohydrate has a mean particle size of 1 μm to 20 μm.
 21. A method of treating rhinitis in a human in need thereof comprising administering by the nasal route to the human the pharmaceutical composition of claim
 19. 